mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor 4E
mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor 4E
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DOI：
10.1128/mcb.24.1.200-216.2004
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发表时间：
2004-01-01
影响因子：
5.3
通讯作者：
Blenis, J
中科院分区：
文献类型：
--
作者：
Fingar, DC;Richardson, CJ;Blenis, J
哺乳动物雷帕霉素靶蛋白（mTOR）整合营养和有丝分裂原信号以调节细胞生长（增加细胞质量和细胞大小）和细胞分裂。免疫抑制药物雷帕霉素通过抑制mTOR来抑制细胞周期进程;然而，mTOR调节细胞周期进程的信号传导途径仍然不清楚。在这里，我们证明了mTOR信号的恢复（通过使用mTOR的雷帕霉素抗性突变体）挽救了雷帕霉素抑制的G（1）期进展，并且沿着mTOR依赖性S6 K1或4 E-BP 1/真核翻译起始因子4 E（eIF 4 E）途径的信号恢复提供了部分挽救。此外，干扰RNA介导的S6 K1表达的降低或阻断eIF 4 E活性的mTOR不敏感的4 E-BP 1亚型的过表达单独地和相加地抑制G（1）期进展。因此，S6 K1和4 E-BP 1/eIF 4 E通路的活性都是mTOR依赖性G（1）期进展所必需的，并独立介导mTOR依赖性G（1）期进展。此外，S6 K1或野生型eIF 4 E的组成型活性突变体的过表达加速了血清刺激的G（1）期进展，并且野生型S6 K1的稳定表达在低血清培养基中赋予了增殖优势，这表明这些途径中的每一种的活性都限制了细胞增殖。这些数据表明，对于细胞生长和细胞大小的调节，S6 K1和4 E-BP 1/eIF 4 E途径各自代表mTOR依赖性细胞周期控制的关键介质。
The mammalian target of rapamycin (mTOR) integrates nutrient and mitogen signals to regulate cell growth (increased cell mass and cell size) and cell division. The immunosuppressive drug rapamycin inhibits cell cycle progression via inhibition of mTOR; however, the signaling pathways by which mTOR regulates cell cycle progression have remained poorly defined. Here we demonstrate that restoration of mTOR signaling (by using a rapamycin-resistant mutant of mTOR) rescues rapamycin-inhibited G(1)-phase progression, and restoration of signaling along the mTOR-dependent S6K1 or 4E-BP1/eukaryotic translation initiation factor 4E (eIF4E) pathways provides partial rescue. Furthermore, interfering RNA-mediated reduction of S6K1 expression or overexpression of mTOR-insensitive 4E-BP1 isoforms that block eIF4E activity inhibit G(1)-phase progression individually and additively. Thus, the activities of both the S6K1 and 4E-BP1/eIF4E pathways are required for and independently mediate mTOR-dependent G(1)-phase progression. In addition, overexpression of constitutively active mutants of S6K1 or wild-type eIF4E accelerates serum-stimulated G(1)-phase progression, and stable expression of wild-type S6K1 confers a proliferative advantage in low-serum-containing media, suggesting that the activity of each of these pathways is limiting for cell proliferation. These data demonstrate that, as for the regulation of cell growth and cell size, the S6K1 and 4E-BP1/eIF4E pathways each represent critical mediators of mTOR-dependent cell cycle control.